Neonatal maladjustment syndrome (NMS) is a common disorder of neonatal foals that manifests within the first 72 h of life (Bernard, et at (1995) In: Proceedings, 41st American Association of Equine Practitioners, Lexington, Ky. pp 222-224; Rossdale and Leadon, (1975) J Reprod Fertil 23, 658-661). The proposed mechanisms include hypoxic and ischaemic events prior to, during and shortly after parturition (Palmer and Rossdale, (1976) Res Vet Sci 20, 267-275). Affected foals exhibit neurological dysfunction such as seizures and altered states of consciousness, behaviour and response to stimuli (Bernard et al. 1995, supra; Ringger, et al. (2011) J Vet Intern Med 25, 132-137). However, hypoxic and ischaemic injury is not always identified upon histopathological evaluation, and long-term neurological deficits have been reportedly rare. Fetal corticosteroids, through activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, contribute to the maturation of many organs and regulate the transition between intra- and extrauterine life (Rossdale, (2004) In: Proceedings, 51st American Association of Equine Practitioners, Denver, Colo. pp 75-126). Rossdale, et al., ((1995) Reprod Fertil Dev 7, 567-575) reported increased concentrations of progestagens in neonatal foals that rapidly decrease over the following 48 h after birth (Houghton, et al., (1991) J Reprod Fert Suppl 44, 609-617; Rossdale 2004, supra). Foals with NMS have been reported to have persistently increased concentrations of plasma progestagens (Houghton et al. 1991, supra; Rossdale et al. 1995, supra; Rossdale 2004, supra). Concentrations of several plasma steroids including progestagens (progesterone and pregnenolone) and androgens (epitestosterone and androstenedione) were found to be significantly increased in foals with NMS compared with healthy foals (Aleman et al, (2013) Equine Veterinary Journal). Certain steroidal compounds called neurosteroids, predominantly 5-α reduced pregnanes, can cross the blood-brain barrier and have neuromodulatory effects (Mellon and Griffin (2002) Trends Endocrinol Metab 13, 35-43; Naert, et al. (2007) Psychoneuroendocrinology 32, 1062-1078). It is proposed that in a subset of foals the signs of NMS may not be the result of hypoxia, and that these neurosteroids may play a role in the aetiology and clinical manifestations of foals with NMS.
NMS has been referred to as hypoxic-ischemic encephalopathy, perinatal asphyxia, neonatal encephalopathy, and dummy foal syndrome (Drummond (1988) Equine Vet J 5, 41-43; Vaala, (1994) Vet Clin N Am Equine Pract 10, 187-218). The proposed pathogenesis is the result of hypoxia and ischemia of the brain which occurs shortly before, during or after parturition leading to neuronal cellular energy failure and death (Drummond (1988) Equine Vet J 5, 41-43; Rossdale (1972) Equine Vet J 4, 117-128; Ringger, et al., (2011) J Vet Intern Med 25, 132-137). Clinical signs are consistent with brain hypoxia and include alterations in the state of consciousness from mild obtundation to stuporous to comatose; abnormal behaviour such as lack of affinity for the mare, not nursing, vocalization, and wandering; blindness; and paroxysmal activity such as paddling and seizures (Palmer and Rossdale (1976) Res Vet Sci 20, 267-275). Histopathological evidence of cerebral hemorrhage and hypoxia has been detected in some severely affected foals (Palmer and Rossdale (1976), supra). However, many foals do not have histological evidence of hypoxia, edema or hemorrhage (Bernard, et al., In: Proceedings, 41st American Association of Equine Practitioners, Lexington, Ky. pp 222-224). Furthermore, many foals have a normal birth and recover quickly and fully from the condition. This is in contrast to infants and newborn rats with asphyxia in which a significantly longer recovery time is needed and long-term neurological deficits are often manifest (Kiss, et al., (2009) Brian Res 1255, 42-50; van Handel, et al., (2007) Eur J Pediatr 166, 645-654). The fast recovery with no apparent long-term deficits and lack of evidence of hypoxia or ischemia in affected neonatal foals suggest that the syndrome may not be exclusively the result of hypoxia.
Neonatal foals have high concentrations of pregnanes at birth which decrease rapidly over the first 48 hours of life (Houghton, et al., (1991) J Reprod Fertil 44, 609-617). Elevated concentrations of plasma pregnanes and a correlation between decreasing levels of pregnanes and clinical recovery have been reported (Rossdale, et al., (1995) Reprod Fertil Dev 7, 567-575). Certain steroidal compounds, predominantly 5-α reduced pregnanes, appear to have important neuromodulatory roles (Baulieu, (1998) Psychoneuroendocrinology 23, 963-987; Mellon and Griffin (2002) Trends Endocrinol Metab 13, 35-43; Robel and Baulieu, (1994) Trends Endocrinol Metab 5, 1-8). These steroids are synthesized de novo in glial cells from cholesterol or blood-borne steroid precursors (Robel, et al., (1994) Trends Endocrinol Metab 5:1-8) and are potent allosteric modulators of the GABAA receptor; low concentrations cause weak enhancement of GABA activity and high concentrations cause complete non-competitive inhibition (Baulieu (1998) Psychoneuroendocrinology 23, 963-987). Infusion of certain 5α-reduced pregnanes into rats and mice (Naert, et al., (2007) Psychoneuroendocrinology 32, 1062-1078; Zhu, et al., (2001) Br J Anaesth 86, 403-412) and neonatal foals (Madigan, et al., (2012) Equine Vet J 44 S41 109-112.) leads to anaesthesia or marked behavioural effects suggesting that these pregnanes cross the blood brain barrier and exert neuromodulatory effects.